Abstract: In order to evaluate the effect of RRE on reducing blood lipid and protecting liver, a model of nonalcoholic fatty liver disease (NAFLD) mice induced by high-fat diet was used, and then the body weight, liver weight and liver coefficient of each group were calculated, and the TC、TG、HDL-C、LDL-C、AST、ALT、AKP were checked by sample test. The liver tissue was stained with HE and oil Red O for pathological observation and fat particles observation; Animal experiment results showed that RRE intervention could effectively improve the process of liver pathological changes, alleviate inflammatory injury and reduce the accumulation of liver fat particles in NAFLD mice; both high and medium doses of RRE could significantly reduce the levels of TC, TG and LDL-C in serum of NAFLD mice (P<0.05), significantly increase the level of HDL-C (P<0.01), and significantly reduce the activities of AST, ALT and AKP in serum of NAFLD mice (P<0.05 or P<0.01); The index levels were better than those of ursolic acid group; RRE low dose group could significantly reduce the levels of TG, LDL-C, AST and in serum of NAFLD mice (P<0.05), and could reduce the levels of TC, ALT and AKP, but there was no significant difference (P>0.05); Through network pharmacology, the intersection of Rhinacanthus nasutus and NAFLD disease-related targets was carried out, and the effective active substances and action mechanism of RRE were predicted combined with molecular docking technology, which showed that rhinacanthin-C had good binding potential with the intersection targets. The experimental results showed that the RRE could reduce blood lipid, improved liver lipid deposition and inflammatory injury in NAFLD mice, so as to protect the liver. Its mechanism may be that the active substance rhinacanthin-C can improve liver lipid deposition and metabolic disorder through AMPK-SREBP1c-SIRT1 signal pathway. The experimental results can provide a scientific basis for the development of Zhuang medicine Rhinacanthus nasutus as a national drug for reducing blood lipid and improving fatty liver.